Viral Hemorrhagic Fevers

Pierre E. Rollin, MDSpecial Pathogens BranchCenters for Disease Control and Prevention

• Acute infection:fever, myalgia, malaise; progression to prostration

• Small vessel involvement:increased permeability, cellular damage

• Multisystem compromise (varies with pathogen)

• Hemorrhage may be small in volume(indicates small vessel involvement, thrombocytopenia)

• Poor prognosis associated with:shock, encephalopathy, extensive hemorrhage

VHF

Differential Diagnosis

• Febrile tropical illnesses:• Malaria• Typhoid fever• Bacterial gastro-enteritis• Rickettsial diseases

Laboratory Diagnosis

• Malaria smears• Blood cultures (closed system)• CBC, especially platelet count• Transaminases (prognostic value)• Creatinine, BUN• Coagulation factors

VHF: Viruses

• Enveloped, single stranded RNA viruses

• Similar syndromes; different pathogenesis & treatment

• Persistent in nature: rodents, bats, ticks, mosquitoes

• Geographically restricted by host

• Potential infectious hazards from laboratory aerosolsFiloviruses Ebola Hemorrhagic fever (Z, S, R, IC, B)

Marburg Hemorrhagic fever Arenaviruses Lassa fever

“New World Arenaviruses”Bunyaviruses Rift Valley fever (RVF)

Crimean Congo Hemorrhagic fever (CCHF)

Ebola

• 1-2 week incubation• Abrupt onset fever, headache, myalgia• GI symptoms, chest pain, delerium• 53-88% case-fatality• ~ 45% hemorrhage• Person-to-person transmission• African rainforest• Unknown reservoir (bat most probable)

Ebola Signs and Symptoms on PresentationEbola Signs and Symptoms on Presentation

0 10 20 30 40 50 60 70 80

EdemaVaginal bleeding

ConvulsionHematuria

HemoptysisAnuria

HiccupsDisorientation

*Bleeding-injection sitesEpistaxis

*Gum bleeding*Rash

Bloody stoolDyspnea

HematemesisRales/rhonchiSplenomegalyHepatomegaly

*Conjunctival injectionBack pain

*Right upper quadrant tenderness*Sore throat

Arthralgia/MyalgiaAbdominal pain

CoughChest pain

Abdominal tendernessNausea/Vomiting

*AnorexiaHeadache*AstheniaDiarrhea

Sign

or S

ympt

om

% Patients

Ebola

Non-Ebola

N = 206

1979, 20041979, 200419941994

1994, 1996, 19961994, 1996, 1996

1976, 19951976, 1995

1996*1996*

20002000

1976, 1979, 2004 1976, 1979, 2004

*Doctor returningfrom Gabon

Ebola Outbreaks

Congo2003

4,0002,000

kilometers

0

DRCDRCDRCDRCDRCDRCDRCDRCDRC(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)

GabonGabonGabonGabonGabonGabonGabonGabonGabon

South AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth Africa

UgandaUgandaUgandaUgandaUgandaUgandaUgandaUgandaUganda

SudanSudanSudanSudanSudanSudanSudanSudanSudanIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory Coast

1995 Zaire

• 315 cases• 81% case-fatality• Point source outbreak• Unrecognized 3 months• 25% health care workers• 2 “super-spreaders”

EHF Risk Factors

2o attack rate of 16%

• Direct physical contactOR = undefined, p<0.01

• Body fluidsOR = 3.8, 95%CI (1.9-6.8)

• No contact = no disease

Suspected EHF cases, DRC, March-June 1995:by Source of Infection

02468

10121416

3/1 3/8 3/15

3/22

3/29 4/5 4/12

4/19

4/26 5/3 5/10

5/17

5/24

5/31 6/7 6/14

6/21

6/28

Date of onset

Num

ber

IDNUM 3IDNUM 2260Other source

02468

10121416

3/1 3/7 3/13

3/19

3/25

3/31 4/6 4/1

24/1

84/2

44/3

0 5/6 5/12

5/18

5/24

5/30 6/5 6/1

16/1

76/2

36/2

9

Date of onset

Num

ber

Non-Healthcare workersHealthcare workers

EHF Cases by Date of Onset and Occupation, Bandundu Region, DRC, 1995

Marburg: Past Outbreaks• 1967Marburg, Frankfurt, & Belgrade25 primary6 secondary7 deathsAfrican green monkeys from Uganda

• 1975Australian travelerZimbabwe1 primary2 secondary1 death

Marburg: Past Outbreaks

• 1980EngineerN.W. Kenya1 primary1 secondary1 death

• 1987Danish travelerW. Kenya1 primary1 death

• 1998-2000Gold mineN.E. DRC76 cases52 deaths>150 cases through

follow-up

Marburg: Past Outbreaks

• 2005Uige, AngolaLargest and deadliest on record374 cases329 deaths88% CFRHome-based injection use

• 20074 casesKitaka mine, UgandaReservoir studies

• 2008Fatal case Netherlandsmild case USA

Uige,Angola ‘05

Durba, DRC ’98-00

Uganda ‘67

Kenya ‘87Kenya ‘80

Zimbabwe ‘75

Uganda,’07,08

02Uganda 2007sep09DRC 1999mayRav Kenya 1987aug3705 Uganda 2007aug

3989 Uganda 2007aug3849 Uganda 2007aug

01Uganda 2007jul4432 Uganda 2007aug3952 Uganda 2007aug4032 Uganda 2007aug3992 Uganda 2007aug

Ozo Zimbabwe 1975feb48 Gabon 2005apr

96 Gabon 2006jan31 Gabon 2005apr

Mus Kenya 1980janPop Germany 1967aug

02DRC 1999apr

1 change

Uganda Bat Sequencesconcatenated

NP and VP35 frags (~700bp)

Max Parsimony

Human isolatesUganda ‘07

04DRC 1999may03DRC 1999apr32DRC 2000aug19DRC 2000feb34DRC 2000aug07DRC 1999may06DRC 1999may

14DRC 2000jan30DRC 2000aug01DRC 1999apr

24DRC 2000apr23DRC 2000mar

29DRC 2000jul27DRC 2000jul

26DRC 2000may

17DRC 2000feb16DRC 2000feb12DRC 2000jan20DRC 2000feb

21DRC 2000feb

22DRC 2000may

18DRC 2000feb

13DRC 2000jan28DRC 2000jul

05DRC 1999may

15DRC 2000feb

33DRC 2000aug25DRC 2000apr

09Angola 2005apr

08Angola 2005apr

04Angola 2005mar

07Angola 2005apr05Angola 2005mar02Angola 2005mar01Angola 2005feb

06Angola 2005apr03Angola 2005mar

11Angola 2005may10Angola 2005apr

R. aegyptiacus

21% virus diversity

Bunyaviruses

• Rift Valley fever• Crimean Congo

hemorrhagic fever• Hemorrhagic fever

with renal syndrome

Rift Valley Fever distribution and outbreaks

Major Outbreaks

Countries at risk

Saudi Arabia 2000

Madagascar 1979, 1990-91, 2008

Mauritania1987, 1998-99, 2002

Egypt 1977-78, 1997-98, 2003

Kenya 1997-98, 2006-07

South Africa 1950-53, 1974-75, 1999, 2008

Somalia 1997-98, 2006-7

Tanzania 1997-98, 2007

Mozambique 1969

Senegal1999, 2002

Gambia1999, 2002

Zambia 1973-74, 1978, 1985

Zimbabwe 1955, 1957, 1969-70, 1978

Namibia 1955, 1974-75

Sudan1973, 2007

Yemen 2000

•Adapted from EFSA Journal (2005) 238, 1-128. “The Risk of a Rift Valley Fever Incursion and its Persistence within the Community"

Rift Valley Fever

• Mosquito-borne (Aedes spp.) vertical transmission in mosquitoes

• Disease of sheep and cattle• Transmission:

• Animal contact (birthing or blood) • Laboratory aerosol

• Mortality 1% overall• Therapy: Ribavirin not recommended• Live-attenuated vaccine (MP-12) undergoing trials

Rift Valley Fever: Clinical features

• 3-7 day incubation, 3-5 day duration

• Asymptomatic or mild illness• Fever, myalgia, weakness, weightloss• Photophobia, conjunctivitis

• Encephalitis• <5% hemorrhagic fever• 1-10% vision loss (retinal hemorrhage, vasculitis)

CLINICAL FEATURES RVF IN SAUDI ARABIA, 2001

VARIABLE n/N (%)

Fever 499/539 (92.6) Nausea 315/530 (59.4) Vomiting 280/532 (52.6) Abdominal pain 202/532 (38.0) Diarrhea 118/530 (22.1) Jaundice 96/530 (18.1) CNS manifestations 81/475 (17.1) Hemorrhagic findings 35/494 (7.1)Vision loss or scotomas 10/683 (1.5)

Vision loss 8/683 (1.2) Scotomas 2/683 (0.3)

From Madani, et al, CID, 2003;37:1084

RVF: Encephalitis

Meningeal signs 67Confusion 81Stupor or coma 78Hypersalivation and teeth grinding 11Hallucinations 43Hemiparesis 5Focal Signs 27CSF pleocytosis 86CSF protein > 40 mg% 57Fatal outcome 11Residua 7

* Percent of total from a series of 37 reported cases

%*%*

1997-1998 East Africa Outbreak

• 478 deaths• 115 VHF deaths• 9% IgM+• ~89,000 cases• 70% animal loss

Rift valley fever outbreak alert and response

0102030405060708090

Num

ber o

f Cas

es

TIME

Animal outbreak

Human outbreak

Control Opportunity

Amplification

Mass Animal Vaccination

Rapid Response

Early DetectionForecasting

Readiness

Courtesy Pierre Formenty WHO

CRIMEAN CONGO HEMORRHAGIC FEVER(CCHF)

• Extensive geographic distribution(Africa, Balkans, and western Asia)

• Transmission:• Tick-borne (Hyalomma spp.) • Contact with animal blood or products• Person-to-person transmission

by contact with infectious body fluids• Laboratory worker transmission documented

• Mortality 15-40%• Therapy: Ribavirin

Distribution of CCHF virus

CCHF: Clinical features

• 4-12 day incubation after tick exposure• 2-7day incubation after direct contact with infected fluids• Abrupt onset fever, chills, myalgia, severe headache• Malaise, GI symptoms, anorexia• Leukopenia, thrombocytopenia, hemoconcentration,

proteinuria, elevated AST• Hemorrhages may be profuse (hematomas, ecchymoses)

PREVENTION OF CCHF

• DEET repellents for skin• Permethrin repellents for clothing –

(0.5% permethrin should be applied to clothing ONLY)• Check for and remove ticks at least twice daily. • If a tick attaches, do not injure or rupture the tick.

Remove ticks by grasping mouthparts at the skin surface using forceps and apply steady traction.

CCHF: Pathogenesis

• Viremia present throughout disease• IFA becomes positive in patients destined to survive days 4-6,

often simultaneously with viremia• Recovery may be due to CMI or neutralizing antibodies• Patients that die usually still viremic• Virus grows in macrophages and other cells• DIC often present• Poor prognosis signaled by early elevated AST and clotting

Arenaviruses

• New world• Junin• Machupo• Guanarito• Sabia• Chapare

• Old world• Lassa• Lujo

Lassa Fever

• West Africa• Rodent-borne (Mastomys natalensis)• Person-to-person transmission

• Direct contact• Sex• Breast feeding

• Mortality 1-3% overall, 20% among hospital patients• Therapy: Ribavirin

Lassa: Clinical features

• 80% asymptomatic

• Fever• Retro-sternal pain• Exudative pharyngitis• Myalgias, headache• Abdominal pain, vomiting• Facial edema and conjunctivitis• Mucosal bleeding• Proteinuria

New WorldArenaviruses

TamiamiSigmodon hispidus

GuanaritoZygodontomys brevicauda

Tacaribe Artibeus bat

AmaparíNeacomys guianae

Sabiá??

OliverosBolomys obscurus

JunínCalomys musculinus

ParanáOryzomys buccinatus

LatinoCalomys callosus

MachupoCalomys callosus

FlexalOryzomys spp.

PinchindéOryzomys albigularis

PiritalSigmodon alstoni

Whitewater Arroyo Neotoma albigula

Bear CanyonPeromycus californicus

CupixiOryzomys capito

AllpahuayoOecomys bicolor

Chapare??

Junin (Argentine hemorrhagic fever)

• Argentine pampas, autumn grain harvest• Rodent borne (Calomys musculinus)• Person-to-person transmission uncommon,

sexual transmission documented.• Mortality 15-30%• Therapy: Immune plasma, Ribavirin(?)

Machupo (Bolivian Hemorrhagic Fever)

• Bolivia, Beni Department• Rodent borne (Calomys callosus)• Person-to-person transmission probable• Mortality 25%• Therapy: Ribavirin(?)

Guanarito (Venezuelan Hemorrhagic Fever)

• Venezuela, central plains• Rodent borne (Zygodontomys brevicauda)• Person-to-person transmission not documented• Mortality 20-30%• Therapy: Ribavirin(?)

South American Hemorrhagic Fevers: Clinical features

• 1-2 week incubation• Gradual onset fever, malaise, myalgias, anorexia• Headache, abdominal pain, nausea, vomiting,

orthostasis• Petechiae (axillae, palate), gingival hemorrhage• Neurologic signs (hyporeflexia, tremor, lethargy,

hyperesthesia)• Leukopenia, thrombocytopenia, proteinuria

South American Hemorrhagic Fevers: Clinical features

• 70% Recovery in 7-8 days without sequelae, prolonged fatigue and weakness common.

• Severe disease• Severe hemorrhage• Delerium, coma, convulsions• Combined hemorrhagic/neurologic disease• High mortality

VHF - Diagnosis

TimeTime33--5 days RVF/CCHF5 days RVF/CCHF55--10 days others10 days others

33--5 days RVF5 days RVF1010--15 days Lassa15 days Lassa

Fever

Virus/Ag/RNA

IgG / Neutralizing Antibody

IgM Antibody

• Rule out or treat febrile illnesses:malaria, rickettsia, leptospirosis, typhoid, dysentery

• Early hospitalization• Distant medical evacuation associated with high mortality• Cautious sedation and analgesia• Careful hydration• Pressors, cardiotonic drugs• Support of coagulation system

VHF: Supportive therapy

Ribavirin

• Guanosine nucleoside analog: blocks viral replication by inhibiting IMP dehydrogenase

• Licensed for treatment of RSV and HCV• Potential adverse effects:

• Dose dependent reversible anemia• Pancreatitis• Teratogen in rodents

• Same regimen: loading dose 30mg/kg (max of 2 grams)16 mg/kg every 6 hours for 4 days8 mg/kg every 8 hours for 6 days

• Post-exposure treatment

Ribavirin: indications

• Filoviruses No• Rift Valley No…• CCHF Yes• Lassa Yes• Argentine HF Yes• Other New/Old world Arena Maybe

Ebola Treatment

Experimental only, require NHP protectionEbola vaccines

DNA Vaccine +Boost Adenovirus (phase II)Adenovirus (phase I)VSVParainfluenza

Marburg vaccinesVEE RepliconVSV

Filovirus Vaccines

VHF: Human-to-Human transmission

• None: Yellow fever, Dengue, Rift Valley fever, Kyasanur, Omsk (arboviruses), hantaviruses

• Low: Lassa and South American Arenaviruses

• High: Ebola, Marburg, Crimean-Congo HF

Standard Precautions

• Constant use of gloves and handwashing(plus face-shields, masks or gowns if splashes are anticipated) for any contact with blood, moist body substances, mucous membranes or non-intact skin.

• Additional, Transmission-based Precautions

Standard Precautions

Transmission-based Precautions•Airborne (TB, Chicken pox, Measles, Smallpox)

•Droplet (Diphtheria, Pertussis, Meningococcus, Influenza, Mumps....)

•Contact (Enteric infections, Respiratory infections, Skin infections, Conjunctivitis…. )

VHF: Contact management

• Casual contacts: e.g., shared airplane or hotel,No surveillance indicated

• Close contacts: Direct contact with patient and/or body fluids during symptomatic illness.Fever watch during incubation period

• High risk contacts: Needle stick, mucosal exposure to body fluids, sexual contact.Fever watch, consider inpatient observation.

Outbreak responseEbola - Marburg

ISOLATION – PPE

Sometimes a woman would clutch his sleeve, crying shrilly:”Doctor, you’ll save him, won’t you?” But he wasn’t there for saving life; he was there to order a sick man’s evacuation. How futile was the hatred he saw on faces then! “You haven’t a heart!” a woman told him on one occasion. She was wrong; he had one. It saw him through his twenty-hour day, when he hourly watched men dying who were meant to live.

(Albert Camus, The Plague, 1947)